The role of mGlu4 receptors within the nucleus accumbens in acquisition and expression of morphine-induced conditioned place preference in male rats

Background Several studies have shown that glutamate neurotransmission in the nucleus accumbens (NAc) is required for the development of morphine-induced conditional place preference (CPP). In addition, metabotropic glutamate receptors (mGluRs) in NAc play important roles in the reward pathways. However, the precise role of mGluR4 in different steps of the morphine-induced CPP is less well known. In the present study the effect of bilateral intra-accumbal infusion of VU0155041, as a specific mGluR4 agonist on the acquisition and expression of morphine induced CPP in male Wistar rats was investigated. The animals were bilaterally implanted with guide cannulae above the NAc. In the first step of the study, the VU0155041 was administered at doses of 10, 30 and 50 μg/0.5 μL saline per side into the NAc during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase of morphine-induced CPP. In the second step of the study, the rats bilaterally received VU0155041 at the dose of 50 μg/0.5 μL, 5 min before the post-conditioning test in order to check the effect of VU0155041 on the expression of morphine-induced CPP. Results The results showed that the intra-accumbal injection of VU0155041 inhibits the acquisition of morphine-induced CPP in a dose dependent manner, but had no effect on expression. Conclusions The data indicated that intra-NAc administration of VU0155041 dose dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine. These effects may be related to changes in glutamate activity in the NAC and/or learning dependent mechanism of glutamate neurotransmission in reward pathway(s).

The Role of mGluR4 Receptors Within the Nucleus Accumbens in the Acquisition and Expression of Morphine-induced Conditioned Place Preference in Male Rats

Background: Several studies have shown that glutamate neurotransmission in the nucleus accumbens (NAc) is required for the development of morphine-induced conditional place preference (CPP). Also, metabotropic glutamate receptors (mGluRs) into the NAc play important roles in the reward pathways. However, the precise role of mGluR4 in different steps of the morphine-induced CPP is less well known. In the present study we investigated the effect of bilateral intra-accumbal infusion of VU0155041, as a specific mGluR4 agonist on the acquisition and expression of morphine induced CPP in male Wistar rats. Animals were bilaterally implanted with guide cannulae above the NAc. In the first part of the study, the VU0155041 was administered at doses of 10, 30 and 50 μg/0.5 μL saline per side into the NAc during the 3 days of morphine (5 mg/kg) conditioning (acquisition) phase of morphine-induced CPP. In the next part of the study, the rats bilaterally received VU0155041 at the dose of 50 μg/0.5 μL, 5 min before the post-conditioning test to check the effect of VU0155041 on the expression of morphine-induced CPP. Results: The results showed that the intra-accumbal injection of VU0155041 inhibits the acquisition of morphine-induced CPP in a dose dependent manner, but had no effect on expression Our data indicated that intra-NAc administration of VU0155041 dose-dependently blocks the establishment of morphine-induced CPP and reduces the rewarding properties of morphine.These effects may be related to changes in glutamate activity in the NAC and/or learning dependent mechanism of glutamate neurotransmission in reward pathway(s).

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

The pharmacogenomic network responsible for the rapid antidepressant action of ketamine and concomitant adverse events in patients has been poorly defined. Integrative, multi-scale biological data analytics helps explain ketamine’s action. Using a validated computational pipeline, candidate ketamine-response genes and regulatory RNAs from published literature, binding affinity studies, and single nucleotide polymorphisms (SNPs) from genomewide association studies (GWAS), we identified 108 SNPs associated with 110 genes and regulatory RNAs. All of these SNPs are classified as enhancers, and additional chromatin interaction mapping in human neural cell lines and tissue shows enhancer-promoter interactions involving other network members. Pathway analysis and gene set optimization identified three composite sub-networks within the broader ketamine pharmacogenomic network. Expression patterns of ketamine network genes within the postmortem human brain are concordant with ketamine neurocircuitry based on the results of 24 published functional neuroimaging studies. The ketamine pharmacogenomic network is enriched in forebrain regions known to be rapidly activated by ketamine, including cingulate cortex and frontal cortex, and is significantly regulated by ketamine (p=6.26E-33; Fisher’s exact test). The ketamine pharmacogenomic network can be partitioned into distinct enhancer sub-networks associated with: (1) glutamate neurotransmission, chromatin remodeling, smoking behavior, schizophrenia, pain, nausea, vomiting, and post-operative delirium; (2) neuroplasticity, depression, and alcohol consumption; and (3) pharmacokinetics. The component sub-networks explain the diverse action mechanisms of ketamine and its analogs. These results may be useful for optimizing pharmacotherapy in patients diagnosed with depression, pain or related stress disorders.One Sentence SummaryThe ketamine network in the human brain consists of sub-networks associated with glutamate neurotransmission, neuroplasticity, and pharmacokinetics.